Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof

Inactive Publication Date: 2018-12-27

CHIA TAI TIANQING PHARMA GRP

0 Cites 0 Cited by

AI-Extracted Technical Summary

Problems solved by technology

Therefore, such processes cannot meet the requi...

Benefits of technology

[0007]One aspect of the present invention provides a sorafenib hemi-p-tosylate monohydrate crystal having a structure represented by formula (11), characterized in that, in a X-ray powder diffraction pattern using Cu Kα irradiation, diffraction peaks occur at 2θ angle of about 5.62, 6.67, 8.05, 9.06, 9.63, 9.91, 10.95, 11.25, 13.48, 14.00, 14.60, 15.08, 15.75, 16.20, 16.62, 16.80, 17.23, 18.40, 18.97, 19.32, 19.82, 20.49, 20.74, 21.51, 22.56, 22.86, 23.37, 23.71, 24.20, 24.71, 24.97, 25.54, 25.80, 26.18, 27.14, 27.48 and 28.29 degree, preferably at 2θ angle of about 5.62, 6.67, 8.05, 9.06, 9.63, 9.91, 10.95, 11.25, 12.79, 13.48, 14.00, 14.60, 15.08, 15.75, 16.20,...

Abstract

The present invention relates to the field of medicinal technology, and in particular, to sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof. The crystal has diffraction peaks occurring at 2θ angle of about 5.62, 6.67, 8.05, 9.06, 9.63, 9.91, 10.95, 11.25, 13.48, 14.00, 14.60, 15.08, 15.75, 16.20, 16.62, 16.80, 17.23, 18.40, 18.97, 19.32, 19.82, 20.49, 20.74, 21.51, 22.56, 22.86, 23.37, 23.71, 24.20, 24.71, 24.97, 25.54, 25.80, 26.18, 27.14, 27.48, and 28.29 degree in a X-ray powder diffraction pattern, and some advantages, such as a high stability, a low hygroscopicity and the like.

Application Domain

Organic chemistryAntineoplastic agents

Technology Topic

Powder diffractionHydrate +3

Image

Examples

Experimental program(4)

Example

Example 1: Preparation of Sorafenib Hemi-p-Tosylate Monohydrate

[0041]At a room temperature, to a reaction tank were added anhydrous ethanol (85.6 kg) and purified water (11.9 kg), and then sorafenib (10.84 kg, 23.32 mol) were added under stirring. After stirring for 10 min, p-toluenesulfonic acid monohydrate (2.38 kg, 12.51 mol) was added at one time. The resulting mixture was crystallized for 8 hours under stirring, and then filtrated under centrifugation. The resulting solid was dried for 10 hours at a temperature of 6035° C. under vacuum to obtain sorafenib hemi-p-tosylate monohydrate (11.48 kg, yield: 89.5% and purity: 99.96%).

[0042]Its X-ray powder diffraction pattern using Cu Kα irradiation was shown in FIG. 1, differential scanning calorimetry (DSC) pattern was shown in FIG. 2, and thermogravimetric analysis (TGA) pattern was shown in FIG. 3.

[0043]Element analysis: C: 51.64% (theoretical value: 51.72%), H: 3.98% (theoretical value: 3.90%), N: 9.83% (theoretical value: 9.85%), S: 2.85% (theoretical value: 2.82%), Cl: 6.29% (theoretical value: 6.23%), F: 10.08% (theoretical value: 10.02%).

Example

Example 2: Liquid Phase Condition for HPLC Analysis of Sorafenib Hemi-p-Tosylate Monohydrate

[0044]Chromatographic column: Agilent peptide map chromatographic column (3.0×150 mm, 2.7 μm)

[0045]Mobile phase A: phosphate buffer solution (monopotassium phosphate (0.79 g) was weighted and dissolved in water, then diluted to 1000 ml, and further adjusted to pH=2.4 with phosphoric acid)

[0046]Mobile phase B: ethanol-acetonitrile (40:60)

[0047]Detection wavelength: 235 nm for detection

[0048]Flow rate: 0.6 ml/min

[0049]Column temperature: 55° C.

[0050]Injection volume: 10 μl

[0051]Solvent: mobile phase A-mobile phase B (1:3)

[0052]Preparation of a solution of a test sample: an appropriate amount of the test sample was weighted and dissolved in the solvent [mobile phase A-mobile phase B (1:3)], then diluted to a solution which comprises about 0.16 mg of sorafenib per 1 ml as the solution of the test sample.

[0053]A linear gradient elution was performed according to the program as shown in Table 3:

TABLE 3 Test condition for HPLC Time (min) Mobile phase A (%) Mobile phase B (%) 0 80 10 12 56.5 43.5 40 10 90 45 80 10 55 80 20

Example

Example 3: Stability Test

[0054]The stability test for the sorafenib hemi-p-tosylate monohydrate crystal of the present invention was conducted according to the Chinese Pharmacopoeia (2010), Part 11, Appendix XIX C: Guideline for Stability Test of Bulk Drug and Pharmaceutical Preparation. The results were shown in Table 4.

TABLE 4 Results of stability test Exposure test to light Shading test Standing for 6 Standing Standing Standing for 10 (luminance: (luminance: months at 25° C. ± for 10 for 10 days at 25° C. 6000 Lux), 6000 Lux), 2° C. and days at days at and humidity of standing for standing for humidity of Day 0 40° C. 60° C. 92.5% ± 5% 10 days 10 days 60% ± 5% Purity 99.96% 99.96% 99.95% 99.96% 99.97% 99.96% 99.96%

[0055]The results in the above table showed that the sorafenib hemi-p-tosylate monohydrate of the present invention is highly stable, and therefore particularly suitable for a pharmaceutical preparation.

PUM

Description & Claims & Application Information

We can also present the details of the Description, Claims and Application information to help users get a comprehensive understanding of the technical details of the patent, such as background art, summary of invention, brief description of drawings, description of embodiments, and other original content. On the other hand, users can also determine the specific scope of protection of the technology through the list of claims; as well as understand the changes in the life cycle of the technology with the presentation of the patent timeline. Login to view more.